Multifunctional nanoscopy for imaging cells

ABSTRACT

Disclosed herein is an apparatus comprising a metal shunt and a semiconductor material in electrical contact with the metal shunt, thereby defining a semiconductor/metal interface for passing a flow of current between the semiconductor material and the metal shunt in response to an application of an electrical bias to the apparatus, wherein the semiconductor material and the metal shunt lie in different planes that are substantially parallel planes, the semiconductor/metal interface thereby being parallel to planes in which the semiconductor material and the metal shunt lie, and wherein, when under the electrical bias, the semiconductor/metal interface is configured to exhibit a change in resistance thereof in response to a perturbation. Such an apparatus can be used as a sensor and deployed as an array of sensors.

CROSS-REFERENCE AND PRIORITY CLAIM TO RELATED PATENT APPLICATIONS

This patent application is a continuation of patent application Ser. No.13/888,065, now U.S. Pat. No. 8,637,944, which is a continuation ofpatent application Ser. No. 12/375,861, now U.S. Pat. No. 8,436,436,which is a national stage entry of PCT patent applicationPCT/US2007/74864, filed Jul. 31, 2007, which claims priority to U.S.provisional patent application 60/821,040, filed Aug. 1, 2006, andentitled “Multifunctional Nanoscopy for Imaging Cells”, the entiredisclosures of each of which are incorporated herein by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

This invention was made with government support under NIH grants such asEB002168, HL042950, and CO-27031 awarded by the National Institutes ofHealth (NIH). The government may have certain rights in the invention

FIELD OF THE INVENTION

The field of this invention relates generally to techniques formeasuring characteristics of an object (such as the cell function andstructure of one or more living cells) on a nanoscale via an array ofintegrated nanosensors that are responsive to various perturbations suchas acoustic waves, light, or electric charge.

BACKGROUND AND SUMMARY OF THE INVENTION

The rapid acquisition and analysis of high volumes of data in biologicalsamples had its advent in the early days of the human genome sequencingproject. Microarray technology has facilitated the interrogation oflarge numbers of samples for biologically relevant patterns in a varietyof physiological, drug-induced or clinically relevant cellular states. Achallenge has now presented itself with respect to how these largevolumes of information can be integrated into an accurate model ofcellular behavior and processes. For example, information relating theeffect of a drug to the extent and duration of apoptosis in cancer cellswould be invaluable information in a screen for cancer drugs. Similarly,information of cytoskeletal changes leading to invasiveness wouldgreatly streamline the development of an efficient anti-angiogenic drugstrategy.

The discipline of cytomics has emerged to meet these and other demandsin both the academic and industrial research communities. The importanceof cytomics derives from the fact that the cell is the minimalfunctional unit within our physiology. An attendant technology to theemergence of cytomics is High Content Screening (HCS) which is generallydefined as a simultaneous, or near real-time, multiparametric analysisof various aspects of cell state.

The complexity of cell function is only part of why cytomics will likelybecome a major field of study in the near future. Every cell isdifferent, and by studying each cell's unique function, that cell typecan be further modeled for subsequent analysis using statisticaltechniques. Within a short time, the inventors herein forecast that mostpharmaceutical companies will not operate without encompassing theessential features of cytomics-drugs-design; a process that willincreasingly operate at the level of modified cellular functions. Futurecancer strategies may place greater emphasis on cytome-alignment orcytomic-realignment, which may be viewed as the “cellular form” oftissue engineering. Such an approach will require a better-than-everunderstanding of how the cell operates, of how to measure cell function,and of how to characterize a live cell in minute detail. To meet thischallenge, there is need in the art for the development of newtechnologies and new analytical tools for exquisitely sensitivesingle-cell analysis.

A primary goal of cytomics is the discovery of functional relationshipsbetween the cell (cytome) and the metabolic pathways (i.e., proteomics,which enables rapid identification of proteins from specific cellpopulations) resulting from genetic control mechanisms (i.e., genomics;some in the art relate cytomics to functional genomics). With cytomics,the amount of information being collected from the cell is expanded inorder to obtain functional data, not just morphological, phenotypic, orgenotypic data.

Currently, there are two major branches of cytomics: analytical cytologyand image cytology. The first, analytical cytology, is comprised oftraditional analytical techniques such as: flow cytometry, single cellanalysis systems and tissue analysis (after cell separation). Thesecond, image cytology (and analysis) is comprised of techniques such as“quantitative” fluorescence assays, high throughput cell culture assays(96-384-1536 well plates), drug effect assays of cytotoxicity,toxicology assays, apoptosis assays, cell proliferation assays, cellploidy assays, and DNA array assays. These techniques are typicallyapplied to single cells, tissues and sections, and cell culture systemsin both 3D and 4D cell culture environments. Laser Scanning Cytometry(LSC) is a well-known example of this type of assay.

At the highest level, cytomics links technology to functional biology atthe cellular level by relating measurement and detection to structureand function. To achieve this end, cytomics integrates tools like flowcytometry, image cytometry, etc. with proteomics and this bringstogether traditional cytometry and non-traditional cytometry. With theapplication of so many different measurement technologies to the sameproblem, informatics now assumes a primary rather than a secondary rolein cytomics. For instance, in a typical flow cytometry system, there are120,000 events per second per output channel, with measurements beingacquired for multiple channels. Another example is offered by very highspeed cell culture plate imaging systems applied to detect fluorescentmarkers in cells.

The term HCS is used to differentiate assays that use live cells and toprovide single point readouts (e.g., High Throughput Screening (HTS)assays), which are often based on the biochemistry of ligand binding.HCS combines cell-based arrays with robotics, informatics, and advancedimaging to provide richly detailed information on cell morphology andother responses in large quantities.

Many protocols for generating data are already well developed in theirrespective disciplines, from quantitative Polymerase Chain Reaction(PCR), to flow cytometry, to antibody staining. The methods foracquisition of this data, such as different types of optical microscopy,have already undergone extensive development. Perhaps the most importantimage acquisition methods for HCS relate to cellular imaging, includingdrug effect assays for cytotoxicity, apoptosis, cell proliferation, andnucleocytoplasmic transport. Frequently, these approaches utilize cellsensors based on fluorescent proteins and dyes, and thus provideresearchers with an ability to screen drugs and to answer more complexbiological questions such as target identification and validation and toinvestigate gene and protein function.

In an effort to fill a need in the art for improved cellular imagingtechniques, the inventors herein disclose a new, inexpensive, andeasy-to-use imaging technology suitable for simultaneous capture ofmultiple measurements from individual cells that will enable molecularcolocalization, metabolic state and motility assessment, anddetermination of cell cycle, texture, and morphology. This technologywill be capable of not only HCS, but also permit selection of singlecells for subsequent high-resolution imaging based on the outputs of theHCS. By increasing the analytical resolution to assess the sub-cellularstate in vivo, the inventors herein hope to increase biologicalresolution by providing a means to follow the location, timing, andinterdependence of biological events within cells in a culture.

The present invention builds upon the previous works by one of theinventors herein, wherein the extraordinary magnetoresistance (EMR) andextraordinary piezoconductance (EPC) properties of hybridsemiconductor/metal devices were used to develop improved sensingtechniques for a wide variety of applications. For EMR devices, examplesinclude but are not limited to read heads for ultra high densitymagnetic recording, position and rotation sensors for machine tools,aircraft and automobiles, flip phone switches, elevator controlswitches, helical launchers for projectiles and spacecraft, and thelike. For EPC devices, examples includes but are not limited to a myriadof pressure sensors, blood pressure monitors, and the like. See U.S.patent application publication 2004/0129087 A1 entitled “ExtraordinaryPiezoconductance in Inhomogeneous Semiconductors”, U.S. Pat. Nos.6,714,374, 6,707,122, 5,965,283, and 5,699,215, Solin et al., Enhancedroom-temperature geometric magnetoresistance in inhomogeneous narrow-gapsemiconductors, Science, 2000; 289, pp. 1530-32; Solin et al.,Self-biasing nonmagnetic giant magnetoresistance sensor, Applied PhysicsLetters, 1996; 69, p. 4105-4107; Solin et al., Geometry driveninterfacial effects in nanoscopic and macroscopic semiconductor metalhybrid structures: Extraordinary magnetoresistance and extraordinarypiezoconductance, Proc. of the International Symposium on Clusters andNanoassemblies, Richmond, 2003; Rowe et al., Enhanced room-temperaturepiezoconductance of metal-semiconductor hybrid structures, AppliedPhysics Letters, 2003; 83, pp. 1160-62; Solin et al., Non-magneticsemiconductors as read-head sensors for ultra-high-density magneticrecording, Applied Physics Letters, 2002; 80, pp. 4012-14; Zhou et al.,Extraordinary magnetoresistance in externally shunted van der Pauwplates, Applied Physics Letters, 2001; 78, p. 667-69; Moussa et al.,Finite element modeling of enhanced magnetoresistance in thin filmsemiconductors with metallic inclusions, Physical Review B (CondensedMatter and Materials Physics) 2001; 64, pp. 184410/1-184410/8; Solin etal., Room temperature extraordinary magnetoresistance of non-magneticnarrow-gap semiconductor/metal composites: Application to read-headsensors for ultra high density magnetic recording, IEEE Transactions onMagnetics, 2002; 38, pp. 89-94; Pashkin et al., Room-temperature Alsingle-electron transistor made by electron-beam lithography, AppliedPhysics Letters, 2000; 76, p. 2256-58; Branford et al., Geometricmanipulation of the high field linear magnetoresistance in InSbepilayers on GaAs (001), Applied Physics Letters, 2005, 86, p.202116/1-202116/3; and Rowe et al, A uni-axial tensile stress apparatusfor temperature-dependent magneto-transport and optical studies ofepitaxial layers, Review of Scientific Instruments, 2002; 73, pp.4270-76, the entire disclosures of each of which being incorporated byreference herein.

The inventors herein extend upon the EMR and EPC sensors referencedabove to disclose arrays comprised of a plurality of individual hybridsemiconductor/metal devices that can be used to measure voltageresponses that are indicative of various characteristics of an objectthat is in proximity to the hybrid semiconductor/metal devices (such asone or more cells, either in vivo or in vitro) and from which images ofthe object characteristics can be generated. These hybridsemiconductor/metal devices may comprise a plurality of EXX sensors on amicroscale or a nanoscale. Preferably, these EXX sensors comprisenanoscale EXX sensors. As used herein, “nanoscale” refers to dimensionsof length, width (or diameter), and thickness for the semiconductor andmetal portions of the EXX sensor that are not greater than approximately1000 nanometers in at least one dimension. As used herein, “microscale”refers to dimensions of length, width (or diameter), and thickness forthe semiconductor and metal portions of the EXX sensor that are notgreater than approximately 1000 micrometers in at least one dimension.The term “EXX sensor” refers to a class of hybrid semiconductor/metaldevices having a semiconductor/metal interface whose response to aspecific type of perturbation produces an extraordinary interfacialeffect XX or an extraordinary bulk effect XX. The interfacial or bulkeffect XX is said to be “extraordinary” as that would term would beunderstood in the art to mean a many-fold increase in sensitivityrelative to that achieved with a macroscopic device for the sameperturbation. Examples of XX interfacial effects include the MR(magnetoresistance) and PC (piezoconductance) effects known fromprevious work by one of the inventors herein as well as EC(electroconductance) effects. It should be noted that AC(acoustoconductance) effects are effectively the same as the PC effectsin that both the EAC and EPC devices can have identical structure. AnEAC device can be thought of as a subset of a class of EPC devices,wherein the EAC device is designed to respond to a strain perturbationthat is produced by an acoustic wave. An example of an XX bulk effectincludes OC (optoconductance) effects. Thus, examples of suitablenanoscale EXX sensors for use in the practice of the present inventioninclude nanoscale EMR sensors, nanoscale EPC sensors, nanoscale EACsensors, nanoscale EOC sensors, and nanoscale EEC sensors.

The inventors herein believe that the use of nanoscale EAC sensors andnanoscale EPC sensors in an imaging array will provide improved imagingresolution, improved signal-to-noise ratio (SNR), and higher bandwidththan conventional ultrasonic or other modes of detectors. Accordingly,the use of an array having a plurality of nanoscale EAC sensors and/or aplurality of nanoscale EPC sensors can be used for a myriad ofapplications, including but not limited to in vitro cell imaging, invivo invasive catheter-based applications for medical imaging,endoscopic imaging for gastrointestinal, prostate, orurethral/bladder/ureteral applications, transdermal medical imaging fordisease characterization, detection of abnormal cells in serum samples,acoustic imaging, pressure sensing in nanofluidics, and blood pressuremonitoring inside small vessels.

The inventors herein further believe that the use of nanoscale EOCsensors in an imaging array will produce ultra high resolution images ofindividual cells or tissues that are indicative of the presence offluorescence in the cells/tissues, a result that can be highly useful inthe investigation of cancer and cancer therapeutics, opticalmicrosccopy, photosensors and photodetectors, image intensifiers,position sensitive detectors, and position and speed control systems.The inventors further believe that additional uses for nanoscale EOCsensors in an imaging array include their use in static chargedetection, EM radiation sensors, and EKG sensors.

The inventors herein further believe that the use of nanoscale EECsensors in an imaging array will produce ultra high resolution images ofelectric charge distribution over the surface of one or more livingcells, a result that can provide valuable information for monitoringcancer metastasis and targeted drug delivery, particularly so when aseries of such images are taken over time to track the progression ofthe cell's electric charge over time. The inventors herein believe thatthe nanoscale EEC sensors of the present invention will serve as asignificantly more accurate and effective measure of cell electriccharge than the conventional electrophoresis technique that is known inthe art because electrophoretic measurements suffer from a complicatedinstrumental dependence and a lack of spatial resolution.

The inventors herein further believe that the use of nanoscale EMRsensors in an imaging array will produce ultra high resolution images ofmagnetoresistance over the surface of one or more living cells, a resultthat can provide valuable information for studying the magnetic fieldsproduced by nonmagnetic particles embedded in cancer cells, formonitoring magnetically labeled nanoparticles that are traffickinginside the cells or for sensing the evolution of imposed magneticresonance spin orientations.

As perhaps the most powerful embodiment of the present invention, theinventors herein envision that a multi-modal array having a plurality ofdifferent types of EXX sensors can be used to simultaneously (or nearlysimultaneously) generate multiple images that are representative ofdifferent characteristics of one or more cells that are imaged by thearray. For example, with a multi-modal array having a plurality of EOCsensors and a plurality of EEC sensors, multiple images can besimultaneously generated that are representative of both fluorescentemissions by the cell(s) and the surface charge of the cell(s). Suchimages would exhibit a nanoscale resolution. As used herein, the term“type” as used in connection with EXX sensors refers to the type of XXinterfacial effect or bulk effect relied upon by the sensor. Forexample, an EAC sensor is of a different type than an EEC sensor.

The inventors further note that the ultra high resolution imagesproduced in the practice of the present invention can not only betwo-dimensional images, but optionally can also be three-dimensionalimages through the use of confocal imaging techniques.

These and other features and advantages of the present invention will bedescribed hereinafter to those having ordinary skill in the art.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of an exemplary EMR/EPC/EAC/EOC sensor;

FIG. 2 is a perspective view of an exemplary EAC sensor that isperturbed by an acoustic perturbation source;

FIG. 3 is a perspective view of an exemplary EOC sensor that isperturbed by a light perturbation source;

FIG. 4 depicts graphs that compares the optoconductance of a shuntedGaAs/In EOC sensor versus a bare GaAs sensor;

FIG. 5 is a graph depicting the temperature dependence of the EOC effectobserved in a GaAs/In EOC sensor;

FIG. 6 depicts a top view of an exemplary EOC sensor showing how leadgeometry can be adjusted;

FIG. 7(a) illustrates a voltage response calculation for a uniformlyilluminated EOC sensor as determined for different voltage leadgeometries;

FIG. 7(b) illustrates a voltage response calculation for an EOC sensorthat is partially covered to achieve nonuniform illumination asdetermined for different voltage lead geometries;

FIG. 7(c) illustrates a plot of a voltage response and an EOC responsefor a uniformly illuminated EOC sensor and a bare semiconductor deviceas a function of the ratio Y_(max)/X_(max);

FIGS. 8(a) and (b) depict a top view and side view for an exemplary EOCsensor having a cover to block light from illuminating a portion of theEOC sensor;

FIG. 9 is a perspective view of an exemplary EEC sensor;

FIG. 10 depicts an I-V curve measured between the shunt and thesemiconductor for an exemplary EEC sensor;

FIG. 11 depicts an EEC measurement for an exemplary EEC sensor;

FIG. 12(a) is a cross-sectional view of an exemplary array of EXXsensors;

FIG. 12(b) is a perspective view of the array of FIG. 12(a);

FIG. 13 depicts schematic diagrams for exemplary multi-EXX sensor arraysshowing various pixel geometries;

FIG. 14(a) is a top view of an exemplary array whose nanosensors areorganized as a plurality of pixels;

FIG. 14(b) is a top view of a pixel corresponding to a plurality ofdifferent types of nanosensors;

FIGS. 15(a) and (b) depict exemplary arrays that show how differentnanosensors can be grouped into composite pixels;

FIG. 16(a) is a cross-sectional view of an exemplary array of EXXsensors having an integral macro-scale PZT transducer;

FIG. 16(b) is a perspective view of the array of FIG. 16(a);

FIG. 17 is a top view of a cell culture dish having an array ofnanoscale EXX sensors incorporated therein;

FIG. 18 depicts an exemplary pitch-catch linear array of multiple PZTtransducers;

FIG. 19 is a flowchart describing an exemplary method for fabricating ananoscale EXX sensor; and

FIG. 20 indicates a synthetic aperture focusing technique applied to aplurality of transmit array elements.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

FIG. 1 illustrates a preferred architecture for a nanoscale EXX sensor100 of the types EMR, EPC, EAC, and EOC. As shown in FIG. 1, nanosensor100 is a hybrid semiconductor/metal device comprising a semiconductorportion 102 and a metal shunt portion 104. The semiconductor 102 and themetal shunt 104 are disposed on a substrate 106. Together, thesemiconductor portion 102 and the metal shunt portion 104 define asemiconductor/metal interface 108. Preferably, the semiconductor portion102 and the metal shunt portion 104 are substantially co-planar as shownin FIG. 1. Furthermore, the semiconductor portion 102 and metal shuntportion 104 preferably lie in a substantially parallel plane as thesubstrate 106. Also, the plane of the semiconductor/metal interface 108is preferably substantially perpendicular to the plane of the substrate106. The architecture of the nanosensor 100 of FIG. 1 is referred to asan externally shunted van der Pauw (vdP) plate.

The semiconductor portion 102 is preferably a thin semiconductor filmhaving a thickness of approximately 1000 nm. However, it should beunderstood that other thickness values can be used, for example athickness in a range between approximately 25 nm and approximately 2000nm. Furthermore, the semiconductor film 102 preferably has a length ofapproximately 100 nm and a width of approximately 50 nm. However, itshould be noted that other lengths and widths for the semiconductor filmcan be used, for example any nanoscale value with a lower limit onlybounded by lithography capabilities (currently believed to be around 5nm, but this lower limit may further decrease with the passage of timeand improvements in technology). As used herein, the term “thickness”will refer to the dimension along the z-axis as shown in FIG. 1, theterm “length” will refer to the dimension along the y-axis as shown inFIG. 1, and the term “width” will refer to the dimension along thex-axis as shown in FIG. 1.

The dimensions for the metal shunt 104 can be a thickness ofapproximately 1000 nm, a length of approximately 100 nm, and a width ofapproximately 100 nm. However, it should be understood that (1) otherthickness values could be used, for example a thickness within a rangeof approximately 25 nm to approximately 2000 nm, and (2) other lengthsand widths could be used, for example any nanoscale length or widthwhose minimum value is only restricted by available lithographytechniques, as noted above. It should also be noted that the dimensionsof the metal shunt 104 relative to the semiconductor film 102 areexpected to be continuously variable, and this relationship defines thefilling factor for the device. Also, relative to the dimensions of thesemiconductor film 102, it should be noted that the width of the shuntis typically less than or equal to the width of the semiconductor film.Typically, the thickness of the shunt will be the same as the thicknessof the semiconductor film, although the shunt may be thinner than thesemiconductor film (normally the shunt would not be thicker than thesemiconductor film).

Preferably, the dimensions of the substrate 106 are much larger than thesemiconductor film and metal shunt. The dimensions for the substrate 106are preferably a thickness of approximately 400 μm and a diameter ofapproximately 2 inches. However, it should be understood that thesevalues can vary considerable based upon the design choices of apractitioner of the invention.

The nanosensor 100 also preferably includes two current leads 110 andtwo voltage leads 112. These leads contact the semiconductor film 102but not the metal shunt 104. Also, these leads preferably contact thesemiconductor film 102 on a surface opposite the semiconductor/metalinterface 108, as shown in FIG. 1. With respect to the geometry of theleads, the two voltage leads 112 are preferably disposed between the twocurrent leads 110 as shown in FIG. 1. Furthermore, the spacing betweenleads is preferably selected in a manner to maximize the extraordinarymagnetoresistance/piezoconductance/acoustoconductance/optoconductanceeffect of the nanosensor 100.

The use of the architecture of FIG. 1 as an EMR sensor and an EPC sensoris known in the art, as explained in the patents and publications citedabove and incorporated by reference herein. However, their principles ofoperation will be briefly re-iterated. The 4-lead effective resistanceof the hybrid semiconductor/metal device 100 of FIG. 1 isR_(eff)=V₂₃/I₁₄, wherein I and V represent the current and voltage leads110 and 112 respectively. The value of R_(eff) will depend on therelative conductivities of the metal 104 and semiconductor 102(typically, σ_(metal)/σ_(semiconductor)>1000), on the resistance of theinterface 108, and on the specific placement of the current and voltageleads (the lead geometry). When the hybrid semiconductor/metal device100 is in a non-perturbed state, the highly conductive metal acts as aneffective current shunt, provided that the resistance of interface 108is sufficiently low, and R_(eff) can be close to that of the metal.However, with a relatively small perturbation such as a change in themagnetic field, pressure/strain or temperature applied to the hybridsemiconductor/metal device 100, a significant change can be induced inthe bulk resistance of the semiconductor 102 and/or the interface 108resistance, and concomitantly the current flow across the interface 108will be significantly altered. These induced changes will manifestthemselves as a relatively large change in R_(eff) which can then beeasily measured via the output voltage signal from the voltage leads 112when a current flow is provided to the hybrid semiconductor/metal device100 via current leads 110.

FIG. 2 illustrates a use of the sensor 100 of FIG. 1 as an EAC sensor.With an EAC nanosensor, the perturbation that results in the measurablevoltage response is an acoustic wave 202. The acoustic wave 202 from anacoustic perturbation source 200 generates a strain at the interface 108that results in a measurable voltage via the extraordinarypiezoconductance effect. In this manner, the EAC sensor is highlysimilar to the EPC sensor. Preferably, the direction of the acousticwave 202 is generally along the z-axis (or perpendicular to the plane ofthe semiconductor film 102 and metal shunt 104 or substantially in thesame plane as the plane of the interface 108).

With an EAC/EPC sensor, the semiconductor/metal interface 108 produces aSchottky barrier to current flow. A tensile (compressive) strain alongthe direction of the interface 108 increase (decreases) the interatomicspacing, thereby increasing (decreasing) the barrier height. Because thetunneling current through the barrier depends exponentially on thebarrier height and any change in that tunneling current is amplified bythe EAC geometry, a small strain results in a large voltagechange/signal. Experimentation by the inventors has shown that thepiezoconductance is largest for an EPC sensor whose geometry ischaracterized by a filling factor of 9/16. See U.S. patent applicationpublication 2002/0129087 A1.

Examples of acoustic perturbation sources that can be used in thepractice of the invention include scanning acoustic microscopes (SAMs),ultrasound emitters using synthetic aperture focusing (SAFT), medicalimagers with phased array transducers or single element focused orunfocused ultrasound transducers, shock wave devices, mid-to-highintensity focused ultrasound arrays, or alternative sources that arecapable of inducing mechanical waves in cells and tissues. As examples,the characteristics of the acoustic perturbation can be as follows: afrequency across the ultra high frequency (UHF) band (300 MHz to 3 GHz,with corresponding wavelengths between 5 μm and 500 nm), a frequency inthe lower portions of the super high frequency (SHF) band (3 GHz to 30GHz, with corresponding wavelengths from 500 nm to 50 nm).

FIG. 3 illustrates a use of the sensor 100 of FIG. 1 as an EOC sensor.With an EOC nanosensor, the perturbation that results in the measurablevoltage response is light 302. The light 302 from a light perturbationsource 300 that impacts the light exposed surfaces of the semiconductorfilm 102 and metal shunt 104 results in a measurable voltage via theextraordinary optoconductance effect. Preferably, the direction ofpropagation for the light 302 is generally along the z-axis (orperpendicular to the plane of the semiconductor film 102 and metal shunt104 or substantially in the same plane as the plane of the interface108). However, as noted below, as the size of the EOC nanosensordecreases, the light will more uniformly illuminate the EOC nanosensordue to the EOC nanosensor's small size.

The light perturbation source 300 can be any source of light emissions,such as a laser emitting device or even a cell with fluorescentemissions (such as would be emitted with the introduction of afluorine-based contrast agent). Further still, the perturbing light canbe electromagnetic radiation, spanning infrared to ultraviolet ranges,with wavelengths measured in the hundreds of nanometers.

FIG. 4 depicts (1) the photo response of a macroscopic GaAs—Insemiconductor-metal hybrid EOC sensor 100 (wherein the semiconductorfilm 102 comprises GaAs and the metal shunt 104 comprises In) (upperpanel) when exposed to a focused Ar ion laser beam of wavelength 476 nm,diameter 10 μm and power 5 mW at 15K, and (2) the photo response ofmacroscopic bare GaAs (without the In shunt) (lower panel) to the samelaser radiation. FIG. 4 plots the optoconductance versus a scan positionof the laser beam along the x-axis of the EOC sensor 100 for a pluralityof discrete scan z positions, wherein the x and z directions arecharacterized by the insets of FIG. 4. The panels of FIG. 4 illustratethree noteworthy characteristics of the EOC sensor: (1) the outputvoltage signal amplitude peaks near the voltage probes 112 (see thepeaks in the voltage response at locations on the x-axis correspondingto the locations of the voltage probes 112), (2) the voltage response ismuch larger (˜500%) for the shunted EOC sensor than for the bare GaAs(thereby demonstrating the EOC effect), and (3) the output voltagesignal amplitude decreases as the focal spot of the laser moves in thez-direction toward the In shunt (which translates to the y-axisdirection in the sensor 100 of FIG. 3).

These EOC effects can be understood as follows. The laser perturbationis absorbed by the semiconductor film 102 and creates a very highdensity of electron-hole pairs that is much larger than the ambient“dark” density. Because the electrons have a much higher mobility, andtherefore a much large mean free path than the holes, the electrons areeffectively shorted to ground by the metal shunt 104, leaving apositively charged region of excess holes that extends radially outwardfrom the center of the impacting laser beam on the surface of the sensor100. This excess positive charge creates an additional electric field atthe voltage leads 112 which results in an enhanced signal as the laserbeam passes the probes 112 along the X-direction. However, as the regionof excess positive charge moves closer to the shunt 104 along theZ-direction (or y-axis of FIG. 3), more and more of the holes are alsoshorted to ground and the excess decreases. This results in a decreasein signal with increasing Z direction laser impact. An additionalcontribution to this decrease comes from the drop off in the excess holeinduced electric field at the voltage contact with the Z directiondistance of the laser spot from those voltage contacts. When there is noshunt 104 present, the electrons cannot be effectively shorted to groundand the amount of excess positive (hole) charge in the region of thelaser spot is significantly reduced.

FIG. 5 plots the temperature dependence of the EOC effect for thesensors of FIG. 4. For the GaAs devices, the EOC effect is mostpronounced at low temperatures because it is at these temperatures thatthe mean free path of the excess electrons is sufficiently long for themto reach and be shorted by the metal shunt 104. The carrier mean freepath is proportional to the carrier mobility which is temperatureindependent and varies inversely with temperature for holes. The plot ofFIG. 5 also shows a least squares fit to the data with a function thatvaries as 1/T where T is the sample temperature in degrees K, therebyindicating the temperature dependence of the EOC effect. On the basis ofthis analysis, we conclude that by using a direct gap but narrow gapsemiconductor (such as InSb; the room temperature mobility of which is70 times that of GaAs) and/or a nanoscopic structure for the EOC sensor,the EOC effect should be realizable at room temperature.

Also, to alleviate any thermal drifts of the output voltage, the InSbsemiconductor can be doped with Si or Te donors so that an extrinsiccarrier concentration in the saturation (e.g., temperature independent)range is achieved.

Also, the inventors note that as the size of the EOC sensor decreases, apoint will be reached where the illumination caused by the lightperturbation source becomes effectively uniform over the EOC sensor.This uniformity would operate to effectively integrate the plot of FIG.4 over the X position, which results in a significant decrease in thestrength of the voltage response from the EOC sensor.

One solution to this problem is to asymmetrically position the leads 110and/or 112 along the x-axis. In one embodiment, such asymmetricalpositioning can be achieved by asymmetrically positioning only thevoltage leads 112 along the x-axis. FIG. 6 depicts a top view of anexemplary EOC sensor 100 showing the semiconductor portion 102, themetal shunt portion 104, and the voltage leads 112 ₁ and 112 ₂(corresponding to the leads V₂ and V₃ from FIG. 3 respectively). Thepositions of the voltage leads 112 along the x-axis are shown in FIG. 6,wherein the full distance along the x-axis for the semiconductor 102 isshown by X_(max). Using the leftmost position along the x-axis in FIG. 6as the origin and the rightmost position along the x-axis as the valueX_(max), it can be seen that the x-axis position of voltage lead 112 ₁is represented by x₁, and that the x-axis position of voltage lead 112,is represented by x₂. The voltage leads are said to be symmetrical if x₁and x₂ exhibit values such that x₂=X_(max)−x₁. To improve the voltageresponse of the EOC sensor 100, it is preferred that the voltage leads112 be asymmetrically positioned along the x-axis.

The voltage potential V₂₃ between voltage leads 112 ₁ and 112 ₂ shown inFIGS. 3 and 6 can be calculated as the integral of the surface chargedensity over the distance to the charge:

${V_{23}\left( {x_{1},x_{2}} \right)} = {\frac{1}{4{\pi ɛ}_{0}}{\int_{0}^{X_{\max}}{\int_{0}^{Y_{\max}}{{{\sigma(y)}\left\lbrack {\frac{1}{\sqrt{\left( {x - x_{1}} \right)^{2} + y^{2}}} - \frac{1}{\sqrt{\left( {x - x_{2}} \right)^{2} + y^{2}}}}\  \right\rbrack}{\mathbb{d}x}\ {\mathbb{d}y}}}}}$wherein Y_(max) is the length along the y-axis for the semiconductorportion 102, wherein σ(y) represents the surface charge density, andwherein ε₀ represents the permittivity of free space. The surface chargedensity σ(y) can be modeled in any of a number of ways. For example, inone model, the assumption is made that uniform illumination creates auniform charge density, which could be represented as:

${\sigma(y)} = {C_{total}\left( {1 + {\frac{1}{2}{\theta\left( {y - y_{s}} \right)}}} \right)}$wherein C_(total) represents the total charge, wherein θ represents thestep (Heaviside) function, wherein the factor ½ is derived from the factthat proximity to the shunt 104 increases the net positive charge as themore mobile electrons are taken to ground more effectively, and whereinthe parameter y_(s) (see FIG. 6) reflects the intrinsic differentialmobility of the material of interest. A large value of y_(s) wouldindicate that all of the mobile carriers have access to ground via theshunt 104, while a small value of y_(s) would indicate that a limitednumber of the mobile carriers have access to ground via the shunt. Inthis model, y_(s) can be the distance along the y-axis as shown in FIG.6 over which it is assumed that the electrons are effectively shunted toground.

Another model can be made for the surface charge density by fitting σ(y)to experimentally measured V₂₃(y) data. In an experiment where V₂₃ wasmeasured for an EOC sensor 100 employing degenerately doped GaAs that isexposed to a focused laser spot for the values of X_(max)=10 mm, x₁=3.4mm, x₂=6.6 mm, and Y_(max)=1 mm, the V₂₃ values for different values ofx₁ and x₂ can be calculated using the formula above for V₂₃ with x and ylimits of integration over a 40 μm square (which approximates lengthscorresponding to the diameter of the laser spot). Because the resultantV₂₃ data from such an experiment indicates that V₂₃(y) is approximatelyGaussian, the integrand in the formula above for V₂₃ must be of theform: y*exp(−y²). Taking in mind a 1/y positional dependence, one cansolve for the experimentally fit σ(y) as follows:

${\sigma(y)}^{fit} = {C_{total}\left( {y + {y^{2}{\mathbb{e}}^{- {(\frac{y - y_{h}}{r_{h}})}}}} \right)}$The effective radii of the Gaussian fit, r_(h), can be 1.5 mm, with anoffset y_(h) of −0.88 mm.

The plot of FIG. 7(a) depicts the calculated voltage output V₂₃ of theEOC sensor 100 assuming a uniform charge density, a fixed Y_(s) of 0.5mm, and a Y_(max)/X_(max) ratio of 1/10. The different lead positions x₁and x₂ are displayed on the xy plane and the voltage is displayed on theordinate. In this plot, the symmetry of the voltage response isapparent. In this plot, the optimal lead position can be defined as the(x₁,x₂) positions of (0 mm,5 mm) and (10 mm, 5 mm) where the voltageresponse is at maximum. These positions, with one lead in the middle ofthe X_(max) distance and the other lead at either end of the X_(max)distance, can be understood qualitatively as the middle lead beingclosest to the most charge compared to the lead on the edge that hasaccess to the least charge.

It should also be noted that in another embodiment, asymmetrical leadpositioning can be achieved by asymmetrically positioning only thecurrent leads 112 along the x-axis. Further still, it should be notedthat asymmetrical lead positioning can also be achieved byasymmetrically positioning both the current leads 110 and the voltageleads 112 along the x-axis.

Another solution to the uniform illumination problem is to shield aportion of the EOC nanosensor that would be exposed to the lightperturbation using a cover 800, as shown in FIGS. 8(a) (top view) and8(b) (side view). In this way, nonuniform illumination can be achievedby blocking some of the light from perturbing the exposed surfaces ofthe semiconductor 102 and metal shunt 104. For example, cover 800 can beused to block half of the otherwise exposed surfaces of thesemiconductor 102 and metal shunt 104. Cover 800 can be formed frommaterials such as a thin film (e.g., 20 nm) layer of an insulator (e.g.,SiO₂) for a bottom surface of the cover 800 followed by a thicker layer(e.g., 50 nm or more) of any metal as an exposed surface of the cover800. As another example, cover 800 can be formed from a single layer(e.g., a 50 nm layer) of any opaque insulator.

The plot of FIG. 7(b) depicts the calculated voltage output V₂₃ of theEOC sensor 100 assuming a uniform charge density, a fixed y_(s) of 0.5mm, and a Y_(max)/X_(max) ratio of 1/10, wherein a cover 800 is used toblock half of the exposed surface of the EOC sensor 100. The differentlead positions x₁ and x₂ are displayed on the xy plane and the voltageis displayed on the ordinate. As can be seen, symmetrical leads can beused without the degradation that one finds in the plot of FIG. 7(a).

Another geometric parameter that is result-effective to increase thevoltage response of the EOC sensor under uniform illumination is theratio Y_(max)/X_(max). This can be seen by way of example in FIG. 7(c).FIG. 7(c) depicts a plot of a calculated output voltage from a uniformlyilluminated EOC sensor as a function of the ratio Y_(max)/X_(max). FIG.7(c) also depicts a plot of an EOC response, wherein the EOC response isdefined as the percent difference in the measured output voltage of theEOC sensor as compared to that of a bare semiconductor sensor. FIG. 7(c)also depicts the voltage response for the bare device as a function ofthe ratio Y_(max)/X_(max).

FIG. 9 illustrates a preferred architecture for a nanoscale EEC sensor900. As shown in FIG. 9, nanosensor 900 is a hybrid semiconductor/metaldevice comprising a semiconductor portion 902 and a metal shunt portion904. The metal shunt portion 904 is disposed on a surface of thesemiconductor portion 902, and the semiconductor portion 902 is disposedon a surface of substrate 906 such that the semiconductor portion 902 issandwiched between the metal shunt portion 902 and the substrate 906. Asshown in FIG. 9, the metal shunt portion 904, the semiconductor portion902, and the substrate portion 906 preferably lie in substantiallyparallel planes. Together, the contact between the metal shunt portion904 and the semiconductor portion 906 define a semiconductor/metalinterface 908. Thus, unlike the nanosensor 100 of FIG. 1, the plane ofthe semiconductor/metal interface 908 of nanosensor 900 is substantiallyparallel with the plane of the metal shunt/semiconductor/substrate.

The semiconductor portion 902 is preferably a thin semiconductor filmhaving a thickness of approximately 1000 nm. However, it should beunderstood that other thickness values can be used, for example athickness in a range between approximately 25 nm and approximately 2000nm, wherein the thickness value is selected to reduce the inputresistance for an improvement in thermal noise reduction andsignal-to-noise ratio. Furthermore, the semiconductor film 902preferably has a length of approximately 100 nm and a width ofapproximately 50 nm. However, it should be noted other nanoscale lengthand width values of the semiconductor film 902 can be used, for examplenanoscale length and widths whose lower limit is only bounded bylithography capabilities.

The dimensions for the metal shunt 904 are preferably a thickness ofapproximately 1000 nm, a length of approximately 100 nm, and a width ofapproximately 50 nm. For an EEC nanosensor, the width and length of themetal shunt 904 are preferably less than or equal to and do not exceedthose of the semiconductor film 902. However, it should once again beunderstood that other thicknesses can be used (for example, any valuewithin a range of approximately 25 nm to approximately 2000 nm, whereinthe thickness value is selected to reduce the input resistance for animprovement in thermal noise reduction and signal-to-noise ratio). Also,the shunt's nanoscale length and width can also be other values selectedso as to not exceed the length and width of the semiconductor film, withthe lower limit bounded only by lithography capabilities.

Preferably, the dimensions of the substrate 906 are sized appropriatelyto support the dimensions of the semiconductor film 902, and as such thesubstrate 906 is typically much larger than the semiconductor film andmetal shunt. Exemplary dimensions for the substrate 906 are preferably athickness of approximately 400 μm and a diameter of approximately 2inches. However, it should be understood that other dimensions could beused.

The nanosensor 900 also preferably includes two current leads 910 andtwo voltage leads 912. These leads contact the semiconductor film 902but not the metal shunt 904. Also, these leads preferably contact thesemiconductor film 902 on a surface along the xz thickness of thesemiconductor film 902, as shown in FIG. 9. With respect to the geometryof the leads, the two voltage leads 912 are preferably disposed betweenthe two current leads 910 as shown in FIG. 9. Furthermore, the spacingbetween leads is preferably selected in a manner to maximize theextraordinary electroconductance effect of the nanosensor 900.

With the EEC nanosensor of FIG. 9, in the absence of an externalperturbing electric field, bias current entering at current lead I₁ andexiting a current lead I₄ will flow primarily through the metal shunt904 due to its much higher conductivity than the semiconductor film 902.However, to access the metal shunt 904, this current must, for theproper choice of materials, tunnel through the Schottky barrier at theinterface 908. This tunneling current varies exponentially with theexternal bias that is applied to the barrier. Thus, if a perturbingelectric field impacts the interface 908 (such as the surface charge ofa cancer cell that is deposited on the surface of the EEC sensor), thenthe perturbing electric charge will be normal to the interface 908. Thisperturbing field will cause a redistribution of the surface charge onthe metal shunt 904, which will result in a bias field applied to theSchottky barrier. The resultant exponential change in tunneling currentwill result in the reapportionment of current flow between thesemiconductor 902 and the metal shunt 904, which will result in a largedetectable change in the voltage measured between voltage leads 912.

The inventors have estimated the magnitude of the electric field thatone can expect from a cancer cell as follows. A claim is commonly madethat normal cell in vivo have a negative charge, and values between −100to −10 mV (which does not have the correct units for charge) are citedin the literature. These voltage values are obtained usingelectrophoresis measurements, which are only indirectly related to theactual cell charge. Frequently, these “charge” measurements are madeusing a turn-key device such as a Zeta-Sizer, which works by using laserlight scattering to measure drift velocity of charged particles in anelectric field (while suspended in a buffer solution). The directlymeasured quantity is the velocity v given by:v=μEwhere E is the applied field (typical value: E˜10⁻¹ V/m), and where μ isthe electrophoretic mobility, a derived quantity that depends on theproperties of the charge particle. For particles having sizes near thoseof a cell, one has:μ=ε_(r)ε₀ζ/η(Smoluchowski's equation) where ε_(r) is the relative permittivity,where η is the viscosity, where ε₀ is the permittivity in vacuo, andwhere ζ is the Zeta potential. For a typical measurement, one has ζ˜10⁻²to 10⁻¹ V, η˜10⁻³ Pas, and ε_(r)˜80, which implies μ˜0.7−7.0×10⁻⁸ m²s⁻¹V⁻¹, which in a typical field of E˜10⁻¹ V/m implies:

$\begin{matrix}{v = {\mu\; E}} \\{= {\left( {0.7 \times 10^{- 8}m^{2}s^{- 1}V^{- 1}\mspace{14mu}{to}\mspace{14mu} 7.0 \times 10^{- 8}m^{2}s^{- 1}V^{- 1}} \right) \times \left( {10^{- 1}v\text{/}m} \right)}} \\{= {0.7 \times 10^{- 9}{ms}^{- 1}\mspace{14mu}{to}\mspace{14mu} 7.0 \times 10^{- 9}{ms}^{- 1}}}\end{matrix}$Assuming that the particles are small, the electric force F that theyexperience is:F=E×qwhere q is the total charge on the particle. This is balanced by theviscous drag of the suspending medium given by:F=6πηRvfor a small spherical particle, of radius R, moving at velocity v, whichis low enough to prevent turbulence. If one assumes a typical cellradius of R˜10⁻⁵ m and use the typical values for v and η cited above,one has:F˜6πηRv=6π×10⁻³ Pas×10⁻⁵ m×0.7−7.0×10⁻⁹ m/s=1.3−13×10⁻¹⁶ NInserting this value into F=Eq above, and using the typical value ofE˜10⁻¹ V/m gives:F:(1.3×10⁻¹⁶ N.to.1.3×10⁻¹⁵ N)≅10⁻¹(V/m)×qwhich solves as q=1.3×10⁻¹⁵ to 13×10⁻¹⁵ coulombs. If one assumes thatthis charge resides on the surface of the cell, it will produce a normalelectric field on the order of 100 V/cm to 1000 V/cm. The inventorsestimate that a field in this range will produce an output voltage of 27to −270 μV in a nanoscale EEC sensor 900 with a 0.5 V forward biasvoltage applied between the metal shunt and output current lead. Thus,the surface charge induced bias field at the semiconductor/metalinterface 908 should be easily detectable in the voltage response of theEEC sensor.

Moreover, in instances where the Schottky barrier of the EEC nanosensoris detrimentally perturbed by chemical impurities at thesemiconductor/metal interface 908, the inventors believe that adding aforward bias voltage to the barrier should alleviate this issue.

FIG. 10 depicts a measured current-voltage plot of a horizontalconfiguration for an EEC sensor 900 having a Schottky barrier interfacebetween GaAs and In as shown in the inset of FIG. 10. The dimensions ofthis EEC sensor were 60 μm×30 μm×50 nm, with respect to the x, y, and zaxes respectively. From this plot, it can be noted that there is anexponential increase of current with forward bias (positive) voltage inthe 0-0.5 V range and that the current is nil in the reverse bias rangeto about −1.5 V. At higher reverse bias, current leakage results asindicated in FIG. 10.

FIG. 11 depicts a measured EEC characteristic of a circular EEC sensoras shown in the inset of FIG. 11. These EEC measurements were made as afunction of the geometric filling factor, α=r/R (see FIG. 11 inset) andof the direct forward and reverse bias on the Schottky barrier forfields in the range of −1050 V/cm to +450 V/cm, as indicated in FIG. 11.It can be noted that the estimates of the field at the surface of acancer cell due to the known total charge of ˜1*10⁻¹⁵ Coulomb is in therange 10²-10⁵V/cm. In this regard, as a quantitative measure of the EECeffect, one can define the EEC effect as:

${EEC} = {100\%\frac{\left\lfloor {G_{w/{field}} - G_{{n/o} \cdot {field}}} \right\rfloor}{G_{{n/o} \cdot {field}}}}$wherein G is the conductance of the EEC sensor, and wherein “with field”means in the presence of the external field that perturbs the EEC sensor(e.g., the field produced by the surface of a cancer cell).

As can be seen in FIG. 11, the EEC depends strongly and increases withfilling factor in both the forward and reverse bias directions, reachingvalues in excess of 50% on saturation in the forward direction. Byselectively doping the semiconductor 902 with Si to tune the propertiesof the Schottky barrier, further improvements to the EEC sensorperformance can be expected.

With respect to these nanoscale EXX sensors, a variety of combinationsof semiconductor materials, metal shunt materials, and substratematerials can be chosen.

For EMR nanosensors, examples of suitable semiconductor materialsinclude InSb, InAs, and Hg_(1-x)Cd_(x)Te, or any narrow gapsemiconductor, and an example of a suitable metal is Au or any goodnon-magnetic metal. Examples of suitable a substrate material for EMRnanosensors include any highly insulating wide gap semiconductor orinsulator, with the preferred material being GaAs both because of itsadvantageous properties and cost.

For EPC and EAC nanosensors, examples of suitable semiconductormaterials include GaAs, InAs or other III-V semiconductors, and examplesof suitable metals include Au or any other high conductivity metal. Withrespect to a substrate material for EPC/EAC nanosensors, the choice ofsubstrate material may vary based on the type of perturbation for thesensor. For example, one can select a “stiff” substrate such as GaAs todetect high frequency, large amplitude acoustic signals, whereas GaSbwould be a more desirable choice for low amplitude, low frequencysignals. Signal selectivity can also be tuned through judicious designof the substrate's dimensional and geometric properties—for example, along, thin and narrow substrate would also be linearly responsive toweak acoustic perturbations while a thick substrate would be morelinearly responsive to stronger acoustic perturbations. In situationswhere both the substrate and semiconductor film are made of GaAsmaterials, the GaAs used in the semiconductor film should have adifferent impurity concentration than the GaAs used in the substrate.

For EOC nanosensors, examples of suitable semiconductor materialsinclude GaAs, InSb, and other direct gap semiconductors, and examples ofsuitable metals include In or any high conductivity metal. Examples of asuitable substrate material include GaAs and other high resistancematerials. Once again, in situations where both the substrate andsemiconductor film are made of GaAs materials, the GaAs used in thesemiconductor film should have a different impurity concentration thanthe GaAs used in the substrate.

For EEC nanosensors, examples of suitable semiconductor materialsinclude GaAs, and other doped semiconductors, and examples of suitablemetals include Au or any other high conductivity metal. Examples of asuitable substrate material include GaAs or any suitably insulatingsubstrate material. Once again, in situations where both the substrateand semiconductor film are made of GaAs materials, the GaAs used in thesemiconductor film should have a different impurity concentration thanthe GaAs used in the substrate.

With respect to providing a current flow to the EXX nanosensors, asuitable biasing current is preferably in a microamp or milliamp rangedepending upon the application and the actual type of EXX sensor.

The nanosensors described above in connection with FIGS. 1-9 can becombined to create an N×M array 1200 of multiple nanoscale EXX sensors1202 as shown in FIGS. 12(a) and 12(b). The values of N and M can bechosen by practitioners of the present invention as a design choicebased on their intended use of the nanoscale EXX sensors (e.g., 4×4,16×16, 2×20, 64×64, etc. with upper values only bounded by manufacturingcapabilities). For example, the inventors contemplate that nanosensormatrix dimensions judging from current digital display technologies canalso be 640×480, 800×600, 1024×768, 1600×1200, 2048×1536, and 3200×2400.These nanoscale EXX sensors 1202 can be deposited on an array substrate1204 such as an SiO₂ substrate. A preferred thickness for substrate 1204is approximately 400 μm, although other thicknesses can be used. Itshould be noted that the voltage and current leads of the individualnanoscale EXX sensors are not shown in FIGS. 12(a) and (b) for ease ofillustration. It should also be noted that a via design for row/columnpin-out addressing from the matrix of nanosensors 1202 in the array 1200can be used, particularly for arrays having large numbers of nanosensors(see FIG. 13). For the array structures shown in FIG. 13, each of the4-leads for the EXX sensors 1202 can be individually addressable,thereby yielding 4n² pin-outs for an n×n array. Furthermore, these leadscan be selectively combined to yield a reduction to 3n+1 pin-outs for ann×n array.

It should also be noted that in instances where the individual EXXsensors are designed to have a substrate 106 of the same material assubstrate 1204, then the EXX sensor 1202 that is located on array 1200will not need to include substrate 106 as the material of substrate 1204can then serve as the appropriate substrate. However, if the substratematerials are dissimilar, then the individual EXX sensors 1202 willpreferably include their own substrate 106 (e.g., when the EXX sensor1202 has a GaAs substrate 106 while the array 1200 has an SiO₂ substrate1204). Preferably, the array 1200 exhibits tight spacing between EXXsensors 1202. For example, a spacing value that falls within a range ofapproximately 50 nm to approximately 1000 nm can be used.

The selection of EXX sensor type(s) and distribution of EXX sensortype(s) over the array 1200 can be highly variable. For example, thearray 1200 can include only nanoscale EXX sensors 1202 of a single type(e.g., an array of only EAC sensors, an array of only EOC sensors, anarray of only EEC sensors, etc.) Also, the array 1200 can include aplurality of different types of nanoscale EXX sensors, such as anycombination of nanoscale EMR/EPC/EAC/EOC/EEC sensors 1202. Integratingmultiple different types of EXX nanosensors in an array (such asEAC/EOC/EEC nanosensors) will provide for a screening system capable ofperforming HCS for prospective interrogation of cells based on theoutcome of charge and fluorescent imaging, like LSC. However, theresolution of the acoustic subsystem will be equal to or greater thanthat obtained from optical microscopy, and moreover will representvolumetric data (i.e., not be limited to a single focal plane at atime), as the time axis of the digitized ultrasound waveforms containsinformation that can be mapped to distance into the cell being imagedvia the dispersion relationship directly analogous to imaging organstructures with currently available clinical ultrasound systems. Thistype of instrumentation would offer several advantages not available incurrent cytometry/microscopy instruments such as simultaneousacquisition of volumetric data based on nanoscale acoustic microscopy,higher resolution than current optical microscopy without necessarilyrequiring expensive high intensity light sources, high precision andresolution surface charge measurements without the complications andambiguities inherent in electrophoretic techniques, and high resolution,low noise fluorescent imaging.

It should also be noted that the array 1200 can be thought of as beingsubdivided into a plurality of pixels 1400, as shown in FIG. 14(a). Eachpixel 1400 can comprise one or more nanosensors 1202. For example, asshown in FIG. 14(b), a pixel 1400 can comprise a plurality of differenttypes of nanosensors 1202, such as 4 nanosensors of types “A”, “B”, “C”,and “D” (wherein type “A” could correspond to an EOC nanosensor, whereintype “B” could correspond to an EPC nanosensor, wherein type “C” couldcorrespond to an EEC nanosensor, and wherein type “D” could correspondto an EMR nanosensor). Such groups of different types of nanosensorswithin a pixel 1400 can be helpful for increasing the sensitivity of thearray 1200 by using signal averaging techniques on the voltage responsesof the nanosensors.

Similarly, it should be noted that pixels 1400 or portions thereof canbe grouped with other pixels 1400 or portions thereof to form compositepixels. For example, FIG. 15(a) depicts a composite pixel 1500 formedfrom a grouping of 4 pixels 1400 of the arrangement shown in FIG. 14(b).Furthermore, the composite pixel 1500 can be formed of only a singletype of nanosensors (e.g. only the “A” type nanosensors within thosefour pixels 1400, as shown by the boldface notation in FIG. 15(a)). Onceagain, such arrangements of composite pixels can be helpful forincreasing sensitivity through the use of signal averaging techniques.

FIG. 15(b) depicts an example of a composite pixel 1502 that is formedfrom a plurality of nanosensors of the same type that are arranged in astraight line and has a length of a plurality of pixels 1400 (e.g., the“A” type nanosensors shown in boldface within composite pixel 1502).FIG. 15(b) also depicts an example of a composite pixel 1504 that isformed from a plurality of nanosensors of the same type that arearranged in a straight line orthogonal to composite pixel 1502 and has alength of a plurality of pixels 1400. Composite pixels arranged such ascomposite pixels 1502 and 1504 can be useful for phase-type imaging ofoptical signals, polarizing deflected light, or detecting differentacoustical modes (e.g., shear, transverse, various plate modes)depending on the type of nanosensor employed.

As an object such as one or more cells is placed into contact with thearray 1200 on the exposed surfaces of the EXX sensors 1202, and as theEXX sensors 1202 of the array are perturbed, the voltage responses ofthe various EXX sensors 1202 can be measured, digitized, stored, andprocessed by receiver electronics including a signal processor (notshown). The collection of voltage responses can in turn be selectivelypixelized based on the spatial relationship among the EXX sensors togenerate an image of the object that is indicative of one or morecharacteristics of the object. Both single-modality images andmulti-modal parameterized images can be generated by registering andcombining the output from different types of nanosensors. Because of thenanoscale of the array's EXX sensors, the resultant images would alsoexhibit a resolution that is nanoscale. Furthermore, each nanoscale EXXsensor 1202 can be independently addressable by the receiver electronicsto permit an increased data acquisition rate (imaging frames of a givenarea of an object per unit time). Also, it should be noted that toenhance the ability of cells to grow and adhere to the array surface,the exposed surface of the array on which the one or more cells contactthe array can be coated with a protein such as fibronectin, vitronectin,collagen, or a protein-mimetic such as poly-1-lysine or silane.

For example, with an array 1200 comprised of multiple EAC and EECsensors 1202, after a cell is placed on that array, the array can beperturbed with an acoustic wave to obtain voltage responses from the EACsensors from which an ultrasonic image of the cell having nanoscaleresolution can be generated. At the same time, the EEC sensors on thearray 1202 can be perturbed with a surface charge from the cell itselfto produce voltage responses from the EEC sensors from which an imagehaving nanoscale resolution and representative of the spatialdistribution of electric charge over the cell can be generated. Further,still, because the surface charge from the cell is not likely to perturbthe EAC sensors and because the acoustic wave is not likely to perturbthe EEC sensors, cross-talk between the EEC and EAC sensors can beminimized, and images of multiple characteristics of the cell can besimultaneously generated.

However, it should be noted that in instances where the array 1200includes both EAC/EPC sensors and EOC sensors, cross-talk can occurwhere the light perturbation causes an undesired voltage response in theEAC sensor and the acoustic perturbation causes an undesired voltageresponse in the EOC sensor. To reduce the effects of such cross-talk,one can selectively perturb the EAC sensors at a different time than theEOC sensors with sequentially applied perturbations and selectiveinterrogation of the nanosensors based on which perturbation has beenapplied. In instances where the cell itself is the source of the lightperturbation (presumably not a spontaneous light emission by the cellbut rather a light emission following exposure to an external opticalfield), cross-talk can be reduced when there is a phosphorescentcomponent present within the cell. In such a case, signal processingtechniques (lock-in amp, digital lock-in, pulse gating, timecorrelation, etc.) can be used to distinguish EAC and EOC signals. ForEOC in the cases of absorption and reflectance the response of the cellwill be essentially instantaneous, e.g. the absorption and reflectionsignals will have essentially the same profile as the incident lightsignal with essentially no phase delay on the time scales of relevancehere. So temporal separation of either absorption or reflection EOC fromEPC should not be problematic. In the case of fluorescence, the EOCsignal will depend on the fluoroescence lifetime of the cell. If this isin the sub microsecond range or shorter, the fluorescence signal can behandled in the same way as absorption and transmission EOC. If it is oforder a millisecond or longer, then an (essentially DC) EOC baselineshift can be added to the EPC signal but the signal above the base lineshould still be easily discernable. The corrollary is applicable fordetection of an EPC signal in the presence of a long lived fluorescence,but by gating the detection system to coincide with the shorter timeacoustic signal the baseline shift can be rejected. There are alsohardware methods to accomplish signal selection. By fabricating asubstrate with thick and thin regions and depositing the EOC sensors onthe thick regions and the EPC sensors on thin ones, the EOC regions canbe made impervious to acoustic signals, whatever their temporalproperties. Similarly, by depositing a thin but optically opaque surfacefilm on only the EPC sensors, they can be made impervious to any opticalsignals regardless of their temporal properties.

The source of the pertubation(s) for the EXX sensors 1202 can be one ormore external perturbation sources as explained above, the object itself(particularly for EOC and EEC nanosensors), or a perturbation sourcethat is integral to the array. For example, a laser source such as anear-field scanning optical microscope (NSOM) can use SAFT techniques tospatially localize a photon field to a small size (on the order of 1micron or less and less than the spacing between EXX sensors on thearray) that can be scanned/driven in X and Y directions across the arrayby the piezoelectric X and Y motion controls of a scanning tunnelingmicroscope (STM) to which the NSOM has been attached/adapted. The STMcould be used to perturb any EAC nanosensors while the NSOM could beused to perturb any EOC nanosensors. The NSOM would guide light from theappropriate laser through a submicron-sized aperture at the end of atapered and metallized optical fiber. The near field method can providephoton fields with a lateral localization as small as 500 nm in thevisible region. Further still, a spatially localized field forperturbing EEC nanosensors could be obtained by mounting a taperedmetallic tip to the STM scanner and applying a known voltage between thetip and a metallized back surface on the substrate 1204. For both thelaser perturbation and the electric field perturbation, the spatialresolution of the applied field would depend on its maintaining closeproximity to the surface of the sensor array. Such proximity can bemaintained by feedback control of the STM's Z-motion via a signal fromthe STM (guiding) tip.

It is also worth noting each of the array's EXX sensors can receive itsown biasing current flow such that not all of the array's EXX sensorswill receive the same current flow. For example, EXX sensors 1-10 of anarray may receive current A while EXX sensors 11-20 of that array mayreceive current B. As a further example, 20 different currents couldalso be delivered to the array's 20 EXX sensors.

FIGS. 16(a) and (b) illustrate another array embodiment for the presentinvention wherein a perturbation source is integral to the array 1600.The array 1600 includes an integral PZT transducer 1604 that serves togenerate the acoustic wave for perturbing the array's EAC/EPCnanosensors 1202. As with the array 1200, the voltage and current leadsof the individual nanoscale EXX sensors 1202 are not shown in FIGS.16(a) and (b) for ease of illustration. However, it should be noted thatground-signal-ground (GSG) wiring geometries for electrical tracesdeposited on substrate 1204 to the nanosensor leads can be employed toimprove characteristics in the UHF and SHF ranges of signal frequencies.With array 1600, the EXX sensors 1202 and substrate 1204 can be arrangedas explained above in connection with FIGS. 12(a) and (b). However, dueto the presence of the PZT transducer 1604, it is preferred that atleast some of the nanoscale EXX sensors 1202 are EPC/EAC sensors. Thearray 1600 also preferably includes a transducer backing material 1608that lies in a plane substantially parallel to the plane of substrate1204. A material and thickness for the backing material 1608 ispreferably selected to have an acoustic impedance that issimilarly-matched to the acoustic impedance of the piezoelectricthin-film transducer 1604 and lossy enough (to attenuate the acousticwave launched into the backing material) to minimize undesired multiplereverberation resonance effects and to “spoil the Q” of the thin-film1604 to effectively broaden the useful frequency bandwidth of the device(corresponding to shorter time pulses and greater axial resolution). Anexample of a backing material 1608 could be an epoxy-resin with groundTungsten particles. However, it should be noted that other backingmaterials may be used as explained above. Furthermore, as the broadbandtransducer gets into the GHz range (rather than the MHz range), theinventors herein believe that the choice of backing materials 1608 maybe less impactful on performance.

Disposed between the substrate 1204 and the backing material 1608 is amacroscale piezoelectric transducer 1604 in contact with a groundconductor 1602 and a hot conductor 1606. The macroscale piezoelectrictransducer 1604 also preferably lies in a plane that is substantiallyparallel to the plane of the substrate 1204. By driving thepiezoelectric transducer 1604 with a current flow through conductors1602 and 1606, the piezoelectric transducer emits a broadband acousticplane wave whose plane is substantially parallel to the plane ofsubstrate 1204 and whose direction of propagation is substantiallynormal to the plane of substrate 1204 (and by derivation in plane withthe plane of the semiconductor/metal interfaces 108 of the EPC/EACnanosensors of the array). This broadband acoustic plane wave serves asthe perturbation for the EPC/EAC nanosensors. The piezoelectrictransducer 1604 can be formed from a thin-film piezoelectric transducermaterial, such as thin-film poly-crystalline or single crystal ofperovskite ceramic materials (e.g., PZT: Lead Zirconate Titanate, anddoped-derivatives such as PNZT: Niobium-doped PZT, PLZT: Lanthanum-dopedPZT, PMN-ZT: magnesium niobate-doped PZT, etc.), or polymer materials(e.g., PVDF: Polyvinylidene difluoride) and exhibit a thickness betweenapproximately 20 nm and approximately 2000 nm to tune the frequencyresponse to a desired range. However, it should be noted that othermaterials and thicknesses can be used. The frequency of the broadbandacoustic plane wave can be in the GHz range (e.g., approximately 1-5GHz), although other frequency values can be used.

The broadband plane wave produced by the macroscale PZT transducer 1604serves to improve the quality of images reconstructed from backscatteredultrasound, and the array 1600 permits insonification of an object beingimaged at pressure levels that would be difficult to obtain using ananoscaled acoustic transmitter. Moreover, by separating the transmitand receive elements (transducer 1604 and nanosensors 1202respectively), the receiving electronics (not shown) can be greatlysimplified to permit higher drive levels on transmit and to improve bothSNR and bandwidth aspects of signal receipt. Furthermore, by integratingboth the transmit and receive elements into a single array, the need forexternal acoustic perturbation sources such as expensive SAMs can beavoided.

The integrated array 1600 or the array 1200 can be mass produced toprovide inexpensive (even disposable) imaging devices that could beincorporated into the bottoms of cell culture dishes 1700 (see FIG. 17),thereby providing the ability to acoustically image either large numbersof or single cells and to continuously provide data that facilitatesmonitoring of the safety and efficacy of therapeutic agents intended fortreatment of diseases such as cancer, heart disease, inflammatoryconditions, etc.

FIG. 18 illustrates another embodiment of an imaging array in accordancewith the present invention. FIG. 18 depicts a multi-element pitch-catcharray 1800. The array 1800 comprises 64 pairs of rectangularpiezoelectric (e.g., PZT or other piezoelectric materials such asdescribed above) elements 1810 that are spaced evenly in a linearconfiguration of opposing pairs 1802 that are 20 μm apart. Base 1806 andsupports 1804 hold the pairs 1802 of PZT elements 1810 in opposition toeach other. Driving electronics (not shown) for delivering power to thePZT elements will also be included in the array 1800. Exemplarydimensions for the piezoelectric elements are 6.0 μm high, 300 nm thick,250 nm wide, and with a 50 nm spacing between elements (for a 300 nmelement pitch and an overall azimuth of 19.2 μm for all 64 elements).However, other dimensions can be used, wherein Sol Gel deposition can beused as a technique to fabricate nanoscale PZT elements.

The 64 PZT elements 1810 (that are shown in a front view in the bottomportion of FIG. 18) are configured to generate ultrasonic pulses thatwill propagate across the 20 μm gap to their opposing partners, whichwill function as receivers. In a pulse/echo mode, the 64 PZT elements onthe opposing side of the array will act as reflectors. An object to beimaged by array 1800 can be placed between the opposing pairs 1802 andultrasound pulses can be used to generate ultrasound data from whichultrasound images of the object can be reconstructed.

Furthermore, an N×M (e.g., 16×16) array like the one shown in FIGS.12(a) and (b) can be made of these PZT elements 1810, fabricated on thenanoscale, for use in the generation of ultrasound images. As with thearrays 1200 and 1600, such an array can be used to generate ultra highresolution images of a cancer cell that is grown on the array surface.Acoustic images of such a cancer cell can be made with ultrasound atfrequencies such as 2.7 GHz or 5.2 GHz using SAFT techniques. To improvesuch an array's SNR, the pulse-repetition frequency of the ultrasoundpulses may be increased, and/or signal averaging techniques can be used.Because the transmit frequency for the preferred ultrasound pulses ishigh (preferably in the GHz range; thereby implying short pulse lengths)and because the round trip distance would be short, the inventors hereinenvision that signal averaging for such arrays will not face the usualproblems that limit signal averaging's utility to conventionalultrasonics. It should also be noted that the arrays 1200 and 1600described above could incorporate nanoscale PZT elements 1810 incombination with the individual EXX sensors 1202 described above.

FIG. 19 depicts a methodology for fabricating nanoscale EXX sensorsusing a multi-step electron beam (e-beam) lithography process At step1900, a thin film wafer of semiconductor material 102/902 is provided.Next at step 1902, a 30 nm thick insulating film of Si₃N₄ (added toprevent shorting between the leads and the shunt) is deposited on thethin film wafer as a cap layer. At step 1904, macroscopic Au strips forwire bonding are deposited on the cap layer in a pattern that radiatesoutward from the edges of an 80 μm square area that is defined on thesubstrate 106/906. Next, at step 1906, a 30 nm thick calixarene film isspin coated onto the surface of the thin film wafer. At step 1908, four30 nm×3 μm Au strips will be delineated in the calixarene in the cornersof the 80 μm square area by e-beam lithography. This calixarene patternand the macroscopic Au strips will serve as a mark for reactive ionetching (RIE) of the Si₃N₄ layer using conventional methods (step 1910).This RIE process (step 1910) produces a raised mesa of the thin film onits supporting substrate. For InSb films, an appropriate etchant is aCH₄+H₂ mixture. The residual Si₃N₄ and Au strips serve as an RIE mask.Then, at step 1912, Au leads and an Au shunt will be deposited using aGe stencil mask and a shadow evaporation technique. The inventorsbelieve that such fabrication will result in EXX nanosensors with avolumetric resolution of 35 nm (the voltage probe spacing set by thelimits of suspended mask e-beam lithography)×30 nm (the width of themesa set by RIE etching properties and the resolution of calixareneresist patterns)×25-250 nm (the thickness of the thin film material,along the x-, y-, and z-axes respectively. See Solin et al., Roomtemperature extraordinary magnetoresistance of non-magnetic narrow-gapsemiconductor/metal composites: Application to read-head sensors forultra high density magnetic recording, IEEE Trans Mag., 2002; 38, pp.89-94; Pashkin et al., Room-temperature Al single-electron transistormade by electron-beam lithography, Applied Physics Letters, 2000; 76, p.2256; M. Sugawara, Plasma Etching, New York; Oxford, 1998, the entiredisclosures of each of which are incorporated by reference herein. Aswould be understood by a person having ordinary skill in the art, thistechnique can be applied to the fabrication of not only EPC, EAC, EOC,EMR, and EOC nanosensors but also EEC nanosensors (although thefabrication of the EEC nanosensors may be less demanding because of thearchitectural difference therebetween).

To minimize leakage current through the floor of the mesa, an insulatingAl₂O₃ barrier can be first prepared by depositing and subsequentlyoxidizing a layer of Al to within 50 nm of the mesa sidewall. Analignment accuracy of about +/−10 nm normal to the mesa sidewall isdesired.

Furthermore, when fabricating an array 1200 or 1000, it is preferredthat the EXX nanosensors 1202 be designed and fabricated together as anarray rather than individually fabricating each EXX nanosensor 1202 andthen aggregating the individual EXX nanosensors 1202 into an array.

Also, when fabricating an array of nanoscale EXX sensors, a substrate1204 thinning process can be used to optimize the array's performance,although this thinning is preferably achieved using afeedback-controlled process that thins the substrate at increasinglyslower and controllable rates to avoid a punch through of the EXXsensors through the substrate. Further still, when fabricating sucharrays of interdigitated nanosensors, several additional mask steps canbe used in the suspended mask e-beam lithography process.

The SAFTs referenced above can be implemented using conventional SAFTsor several variants thereof, wherein the variants of the conventionalSAFT algorithm reduce the number of array elements required and offerimprovements in SNR. These variants include multielement-subapertureSAFT (see Gammelmark et al., “Multielement synthetic transmit aperturnimaging using temporal encoding”, IEEE Transactions on Medical Imaging,2003; 22, pp. 552-63, the entire disclosure of which is incorporatedherein by reference), which has been shown to achieve higher electronicsignal to noise ratio and better contrast resolution than theconventional synthetic aperture focusing techniques. Another SAFTapproach is based on sparse array SAFT which offers the advantage of areduction in the number of array elements (obtained at the price oflower transmitted and received signal). These drawbacks can be minimizedby increasing the power delivered to each transmit element and by usingmultiple transmit elements for each transmit pulse. Another SAFT optionis to use a combination of B-mode and SAFT that has been shown toimprove lateral resolution beyond the focus of the transducer and byusing apodization to lower the sidelobes, but only at the expense oflateral resolution, as with classical synthetic aperture imaging.Results obtained by this technique show that, for a 15 MHz focusedtransducer, the 6-dB beamwidths at 3, 5, and 7 mm beyond the focus are189 μm, 184 μm, and 215 μm, respectively. For images made by scanning a0.12 mm wire, SNR is 38.6 dB when the wire is at the focus, and it is32.8 dB, 35.3 dB and 38.1 dB after synthetic aperture processing whenthe wire is 3, 5, and 7 mm beyond the focus, respectively. At 1-2 GHz,these beamwidths and SNRs imply resolution would scale down to thenanometer range.

FIG. 20 shows an approach to synthetic aperture imaging that followsFrazier's description. FIG. 20 depicts an array of elements labeled bythe index i. In order to simplify the description, only the receive sideof the imaging problem where each element is fired simultaneously willbe considered. It is desired to process the backscattered signalsS_(i)(t) measured at each array element so that those signals areeffectively focused at the point P. This may be achieved byappropriately delaying various signals from the array elements andsumming them (“delay-and-sum” beam forming). The field from the arraywill be focused at the point P if all pulses from the array elementsarrive there simultaneously. This can be effected in post-processing ifone shifts each backscattered pulse byΔt _(i)=2z/c(1−√{square root over (1+(id/z))})and then summing each of the received waveforms according to:Δ(t)=Σw _(i)(P)S _(i)(t−Δt _(i))where the w_(i)(P) terms are weights assigned to each element and arefunctions of the chosen focal point P and also array element transmitproperties that affect the field it transmits. These weights are used toachieve aperture apodization, which is necessary to obtain increasedresolution. The inventors have obtained satisfactory results using aunit rectangle function whose width is determined by the transducer usedto acquire raw data. See Bracewell, R N, The Fourier Transform and itsApplications, New York, McGraw-Hill, 1978, the entire disclosure ofwhich is incorporated by reference herein. For applications where higherresolution is desired such as with the nanosensors described herein,other apodizations such those described by Frazier can be used.

While the present invention has been described above in relation to itspreferred embodiment, various modifications may be made thereto thatstill fall within the invention's scope. Such modifications to theinvention will be recognizable upon review of the teachings herein. Forexample, the nanosensor embodiments described herein have been describedas having a generally rectangular plate shape. It should be noted thatother geometries could be used for the nanosensors. For example, acircular semiconductor material with an embedded concentric metallicshunt. Also, it should be noted that the inventors envision that thenanoscale EXX sensors and/or arrays of such nanoscale EXX sensors can beimplanted into a patient's body (such as within a patient's vasculature)for imaging internal bodily conditions of the patient. These sensors orarrays could be implanted in much that same way that subcutaneous pumps,or cardiac pacemakers and defibrillators, or the routes for anyprosthetic device are implanted. The inventors contemplate that deliveryand deployment via intravascular catheters would be used. Suchnanosensors and arrays can be configured with a telemetric output, suchas by transmitters incorporated into the arrays that produce signals(e.g. radio signals) that can be monitored remotely with appropriatereceivers, as it the case with implanted pacemakers, to provide in vivoultra high resolution imaging of internal body conditions and processesor they can include on-board local memory in which the voltage responsescan be stored for subsequent analysis upon retrieval of the array. Forbiasing currents, the nanosensors or arrays can be configured with theirown on board energy sources.

Further still, the nanosensors and arrays of the present invention mayalso be used for other non-medical applications, including but notlimited to real-time in-process monitoring of any nanoscale eventsdetectable by the sensors and incorporation into field sensors forenvironmental monitoring. For example, the inventors envision thatnanoscale EOC sensors can be useful as position sensitive detectors andas photosensors and that nanoscale EEC sensors can be useful for pixelmonitoring in flat panel displays.

Accordingly, the full scope of the present invention is to be definedsolely by the appended claims and their legal equivalents.

What is claimed is:
 1. An apparatus comprising: a metal shunt; and asemiconductor material in electrical contact with the metal shunt,thereby defining a semiconductor/metal interface for passing a flow ofcurrent between the semiconductor material and the metal shunt inresponse to an application of an electrical bias to the apparatus;wherein the semiconductor material and the metal shunt lie in differentplanes that are substantially parallel planes, the semiconductor/metalinterface thereby being parallel to planes in which the semiconductormaterial and the metal shunt lie; and wherein, when under the electricalbias, the semiconductor/metal interface is configured to exhibit achange in resistance thereof in response to a perturbation.
 2. Theapparatus of claim 1 wherein the change in resistance is indicative of acharacteristic of an object in proximity to the apparatus.
 3. Theapparatus of claim 1 wherein the metal shunt partially covers thesemiconductor material surface such that a portion of the semiconductormaterial surface is uncovered by the metal shunt and another portion ofthe semiconductor material surface is covered by the metal shunt.
 4. Theapparatus of claim 1 wherein the semiconductor material comprises a mesaportion, and wherein the metal shunt is located on the mesa portion ofthe semiconductor material.
 5. The apparatus of claim 1 wherein thesemiconductor material comprises a semiconductor film, the semiconductorfilm having a thickness in a range of approximately 25 nm toapproximately 2000 nm, wherein the metal shunt has a thickness in arange of approximately 25 nm to approximately 2000 nm, and wherein themetal shunt has a lateral dimension that is less than or equal to alateral dimension of the semiconductor film.
 6. The apparatus of claim 2wherein, when under the electrical bias, the semiconductor/metalinterface is configured to exhibit the change in resistance thereof inresponse to an electric field perturbation.
 7. The apparatus of claim 3wherein the metal shunt has a thickness in a range of approximately 25nm to approximately 2000 nm.
 8. The apparatus of claim 7 wherein thesemiconductor material comprises a semiconductor film, the semiconductorfilm having a thickness in a range of approximately 25 nm toapproximately 2000 nm.
 9. The apparatus of claim 8 wherein thesemiconductor film has a nanoscale lateral dimension.
 10. The apparatusof claim 9 wherein the semiconductor film exhibits a circular orrectangular shape.
 11. The apparatus of claim 9 wherein thesemiconductor film comprises a member of the group consisting of GaAsand other doped semiconductors.
 12. The apparatus of claim 9 furthercomprising a plurality of leads in contact with the semiconductormaterial but not the metal shunt, the leads configured to (1) providethe electrical bias to the apparatus and (2) communicate a measurablevoltage response in response to the perturbation, the voltage responsebeing indicative of the resistance change of the semiconductor/metalinterface.
 13. The apparatus of claim 9 further comprising the object incontact with the apparatus, wherein the object comprises at least oneliving cell.
 14. The apparatus of claim 12 wherein the plurality ofleads comprise a plurality of current leads and a plurality of voltageleads.
 15. The apparatus of claim 12 wherein the semiconductor/metalinterface is configured as a Schottky barrier; wherein, when under theelectrical bias with no perturbation, a portion of current entering thesemiconductor material will tunnel through the Schottky barrier to flowthrough the metal shunt; and wherein, when under the electrical biaswith the perturbation, the Schottky barrier will change to cause achange to the tunneling current, thereby causing a reapportionment ofcurrent flow between the semiconductor material and the metal shuntwhich exhibits itself via the measurable voltage response.
 16. Theapparatus of claim 4 wherein the metal shunt partially covers the mesaportion of the semiconductor material.
 17. The apparatus of claim 5wherein the lateral dimension of the metal shunt is less than thelateral dimension of the semiconductor film.
 18. The apparatus of claim17 wherein the semiconductor/metal interface is configured as a Schottkybarrier; wherein, when under the electrical bias with no perturbation, aportion of current entering the semiconductor material will tunnelthrough the Schottky barrier to flow through the metal shunt; andwherein, when under the electrical bias with the perturbation, theSchottky barrier will change to cause a change to the tunneling current,thereby causing a reapportionment of current flow between thesemiconductor material and the metal shunt.
 19. An apparatus comprising:a metal shunt; and a semiconductor material, wherein the semiconductormaterial and the metal shunt lie in different planes that aresubstantially parallel planes; an interface sandwiched between the metalshunt and the semiconductor material, the interface for passing a flowof current between the semiconductor material and the metal shunt inresponse to an application of an electrical bias to the apparatus; andwherein, when under the electrical bias, the interface is configured toexhibit a change in resistance thereof in response to a perturbation.20. The apparatus of claim 19 wherein the interface is configured as aSchottky barrier; wherein, when under the electrical bias with noperturbation, a portion of current entering the semiconductor materialwill tunnel through the Schottky barrier to flow through the metalshunt; and wherein, when under the electrical bias with theperturbation, the Schottky barrier will change to cause a change to thetunneling current, thereby causing a reapportionment of current flowbetween the semiconductor material and the metal shunt which exhibitsitself via a measurable voltage response for the apparatus.
 21. Theapparatus of claim 20 wherein the metal shunt partially covers thesemiconductor material, wherein the metal shunt comprises a nanoscalemetal shunt, and wherein the semiconductor material comprises ananoscale semiconductor material.
 22. An apparatus comprising: an arraycomprising a plurality of sensors, wherein each of at least a pluralityof the sensors comprises: a metal shunt; and a semiconductor material inelectrical contact with the metal shunt, thereby defining asemiconductor/metal interface for passing a flow of current between thesemiconductor material and the metal shunt in response to an applicationof an electrical bias to the sensor; wherein the semiconductor materialand the metal shunt lie in different planes that are substantiallyparallel planes, the semiconductor/metal interface thereby beingparallel to the planes in which the semiconductor material and the metalshunt lie; and wherein, when under the electrical bias, thesemiconductor/metal interface is configured to exhibit a change inresistance thereof in response to a perturbation; and receiverelectronics in cooperation with the array, the receiver electronicsconfigured to (1) receive a plurality of voltage responses from thesensors while an object is in a location detectable by the array, thevoltage responses corresponding to the resistance changes caused by theperturbation, and (2) process the received voltage responses to generatean image of the object based on the processed voltage responses.
 23. Theapparatus of claim 22 wherein, for each of at least a plurality of thesensors, the semiconductor material comprises a mesa portion, andwherein the metal shunt partially covers the mesa portion of thesemiconductor material.
 24. The apparatus of claim 22 wherein, for eachof at least a plurality of the sensors, the metal shunt partially coversthe semiconductor material such that a portion of the semiconductormaterial surface is uncovered by the metal shunt and another portion ofthe semiconductor material surface is covered by the metal shunt. 25.The apparatus of claim 24 wherein, for each of at least a plurality ofthe sensors, the semiconductor material comprises a semiconductor film,the semiconductor film having a thickness in a range of approximately 25nm to approximately 2000 nm, and (2) a nanoscale lateral dimension, andwherein the metal shunt has a thickness in a range of approximately 25nm to approximately 2000 nm; and wherein the generated image exhibits ananoscale resolution.
 26. The apparatus of claim 25 wherein, for each ofat least a plurality of the sensors, the semiconductor/metal interfaceis configured as a Schottky barrier, wherein, when under the electricalbias with no perturbation, a portion of current entering thesemiconductor material will tunnel through the Schottky barrier to flowthrough the metal shunt, and wherein, when under the electrical biaswith the perturbation, the Schottky barrier will change to cause achange to the tunneling current, thereby causing a reapportionment ofcurrent flow between the semiconductor material and the metal shuntwhich exhibits itself via the voltage response for that sensor.
 27. Theapparatus of claim 25 wherein the perturbation comprises an electricfield perturbation.
 28. A method of sensing a characteristic of anobject, the method comprising: perturbing a sensor while an object is ina location detectable by the sensor, the sensor comprising: a metalshunt; and a semiconductor material in electrical contact with the metalshunt, thereby defining a semiconductor/metal interface for passing aflow of current between the semiconductor material and the metal shuntin response to an application of an electrical bias to the sensor;wherein the semiconductor material and the metal shunt lie in differentplanes that are substantially parallel planes, the semiconductor/metalinterface thereby being parallel to the planes in which thesemiconductor material and the metal shunt lie; and wherein the sensoris under the electrical bias, and wherein the semiconductor/metalinterface is configured to exhibit a change in resistance thereof inresponse to a perturbation, the resistance change being indicative of acharacteristic of the object; and measuring a voltage from the sensor inresponse to the perturbing step, the measured voltage responsecorresponding to the resistance change such that the measured voltageresponse is indicative of the object characteristic.
 29. The method ofclaim 28 wherein the metal shunt has a thickness in a range ofapproximately 25 nm to approximately 2000 nm, and wherein thesemiconductor material has a thickness in a range of approximately 25 nmto approximately 2000 nm.
 30. The method of claim 29 wherein thesemiconductor material has a nanoscale lateral dimension.
 31. The methodof claim 30 wherein the metal shunt partially covers the semiconductormaterial surface such that a portion of the semiconductor materialsurface is uncovered by the metal shunt and another portion of thesemiconductor material surface is covered by the metal shunt.
 32. Themethod of claim 31 wherein the semiconductor material comprises a mesaportion, and wherein the metal shunt partially covers the mesa portionof the semiconductor material.
 33. The method of claim 31 furthercomprising a plurality of leads in contact with the semiconductormaterial, the leads configured to (1) provide the electrical bias to thesensor and (2) communicate the voltage for the measuring step.
 34. Themethod of claim 31 wherein the semiconductor/metal interface isconfigured as a Schottky barrier such that when the sensor is under theelectrical bias with no perturbation, a portion of current enters thesemiconductor material and tunnels through the Schottky barrier to flowthrough the metal shunt; and wherein the perturbing step causes theSchottky barrier to change, thereby causing a change to the tunnelingcurrent, the changed tunneling current resulting in a reapportionment ofcurrent flow between the semiconductor material and the metal shuntwhich exhibits itself via the voltage response.
 35. The method of claim31 wherein the sensor comprises a plurality of the sensors formed intoan array, wherein the perturbing step comprises perturbing a pluralityof the sensors in the array, and wherein the measuring step comprisesmeasuring the voltage responses from the perturbed sensors.
 36. Themethod of claim 33 wherein the plurality of leads comprise a pluralityof current leads and a plurality of voltage leads.
 37. The method ofclaim 35 further comprising: generating, by receiver electronics, animage corresponding to the object characteristic from the measuredvoltage responses, the image exhibiting a nanoscale resolution.
 38. Themethod of claim 35 further comprising: electrically biasing the sensorsof the array.
 39. The method of claim 35 wherein the perturbing stepcomprises perturbing the array with a perturbation produced by theobject.
 40. The method of claim 35 wherein the perturbing step comprisesperturbing the array with an electric field.
 41. The method of claim 35wherein the object comprises a plurality of pixels in a flat paneldisplay.
 42. The method of claim 39 wherein the object comprises a cell.43. The method of claim 42 wherein the perturbation comprises anelectric field produced by a living cell.